Polymorphic tandem repeats shape single-cell gene expression across the immune landscape DOI Creative Commons
Hope A. Tanudisastro, Anna Cuomo, Ben Weisburd

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Abstract Tandem repeats (TRs) – highly polymorphic, repetitive sequences dispersed across the human genome are crucial regulators of gene expression and diverse biological processes. Yet, due to historical challenges in their accurate calling analysis, TRs have remained underexplored compared single nucleotide variants (SNVs). Here, we introduce a cell type-specific resource exploring impact TR variation on expression. Leveraging whole single-cell RNA sequencing, catalog over 1.7 million polymorphic loci associations with more than 5 blood-derived cells from 1,790 individuals. We identify 58,000 quantitative trait (sc-eTRs), 16.6% which specific one 28 distinct immune types. Further fine-mapping uncovers 6,210 sc-eTRs as candidate causal drivers 21% genes tested genome-wide. show through colocalization that likely 2,000 GWAS associated immune-mediated hematological traits, further novel warranting investigation rare disease cohorts. pivotal, yet long-overlooked, contributors expression, promising implications for understanding pathogenesis genetic architecture complex traits.

Language: Английский

Sequencing and characterizing short tandem repeats in the human genome DOI
Hope A. Tanudisastro, Ira W. Deveson, Harriet Dashnow

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(7), P. 460 - 475

Published: Feb. 16, 2024

Language: Английский

Citations

40
Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications DOI
Indhu‐Shree Rajan‐Babu, Egor Dolzhenko, Michael A. Eberle

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(7), P. 476 - 499

Published: March 11, 2024

Language: Английский

Citations

27
Characterization of genome-wide STR variation in 6487 human genomes DOI Creative Commons
Yirong Shi, Yiwei Niu, Peng Zhang

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 12, 2023

Short tandem repeats (STRs) are abundant and highly mutagenic in the human genome. Many STR loci have been associated with a range of genetic disorders. However, most population-scale studies on variation humans focused European ancestry cohorts or limited by sequencing depth. Here, we depicted comprehensive map 366,013 polymorphic STRs (pSTRs) constructed from 6487 deeply sequenced genomes, comprising 3983 Chinese samples (~31.5x, NyuWa) 2504 1000 Genomes Project (~33.3x, 1KGP). We found that mutations were affected motif length, chromosome context epigenetic features. identified 3273 1117 pSTRs whose repeat numbers gene expression 3'UTR alternative polyadenylation, respectively. also implemented population analysis, investigated differentiated signatures, genotyped 60 known disease-causing STRs. Overall, this study further extends scale propels our understanding semantics

Language: Английский

Citations

41
A deep population reference panel of tandem repeat variation DOI Creative Commons
Helyaneh Ziaei Jam, Yang Li, Ross DeVito

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 23, 2023

Abstract Tandem repeats (TRs) represent one of the largest sources genetic variation in humans and are implicated a range phenotypes. Here we present deep characterization TR based on high coverage whole genome sequencing from 3550 diverse individuals 1000 Genomes Project H3Africa cohorts. We develop method, EnsembleTR, to integrate genotypes four separate methods resulting high-quality at more than 1.7 million loci. Our catalog reveals novel sequence features influencing heterozygosity, identifies population-specific trinucleotide expansions, finds hundreds eQTL signals. Finally, generate phased haplotype panel which can be used impute most TRs nearby single nucleotide polymorphisms (SNPs) with accuracy. Overall, reference generated here will serve as valuable resources for future genome-wide population-wide studies their role human

Language: Английский

Citations

41
Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer DOI Creative Commons
Ronen E. Mukamel, Robert E. Handsaker, Maxwell A. Sherman

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(17), P. 3659 - 3673.e23

Published: July 31, 2023

Many regions in the human genome vary length among individuals due to variable numbers of tandem repeats (VNTRs). To assess phenotypic impact VNTRs genome-wide, we applied a statistical imputation approach estimate lengths 9,561 autosomal VNTR loci 418,136 unrelated UK Biobank participants and 838 GTEx participants. Association fine-mapping analyses identified 58 that appeared influence complex trait Biobank, 18 which also modulate expression or splicing nearby gene. Non-coding at TMCO1 EIF3H generate largest known contributions common genetic variation risk glaucoma colorectal cancer, respectively. Each these two associated with >2-fold range across individuals. These results reveal substantial previously unappreciated role non-coding health gene regulation.

Language: Английский

Citations

25
Protein-altering variants at copy number-variable regions influence diverse human phenotypes DOI Creative Commons
Margaux L.A. Hujoel, Robert E. Handsaker, Maxwell A. Sherman

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(4), P. 569 - 578

Published: March 28, 2024

Abstract Copy number variants (CNVs) are among the largest genetic variants, yet CNVs have not been effectively ascertained in most association studies. Here we protein-altering from UK Biobank whole-exome sequencing data ( n = 468,570) using haplotype-informed methods capable of detecting subexonic and variation within segmental duplications. Incorporating into analyses rare predicted to cause gene loss function (LOF) identified 100 associations LOF with 41 quantitative traits. A low-frequency partial deletion RGL3 exon 6 conferred one strongest protective effects on hypertension risk (odds ratio 0.86 (0.82–0.90)). Protein-coding rapidly evolving families duplications—previously invisible analysis methods—generated some human genome’s contributions type 2 diabetes risk, chronotype blood cell These results illustrate potential for new insights genomic that has escaped large-scale date.

Language: Английский

Citations

15
WebSTR: A Population-wide Database of Short Tandem Repeat Variation in Humans DOI Creative Commons
Oxana Lundström, Max A. Verbiest, Feifei Xia

et al.

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(20), P. 168260 - 168260

Published: Sept. 7, 2023

Short tandem repeats (STRs) are consecutive repetitions of one to six nucleotide motifs. They hypervariable due the high prevalence repeat unit insertions or deletions primarily caused by polymerase slippage during replication. Genetic variation at STRs has been shown influence a range traits in humans, including gene expression, cancer risk, and autism. Until recently have poorly studied since they pose significant challenges bioinformatics analyses. Moreover, genome-wide analysis STR population-scale cohorts requires large amounts data computational resources. However, recent advent tools resulted multiple datasets spanning nearly two million genomic loci thousands individuals from diverse populations. Here we present WebSTR, database genetic other characteristics across human WebSTR is based on reference panels more than 1.7 created with state art annotation methods can easily be extended include additional species. It currently contains genotypes for 1000 Genomes Project, H3Africa, Genotype-Tissue Expression (GTEx) Project colorectal patients TCGA dataset. implemented as relational programmatic access available through an API web portal browsing data. The publicly https://webstr.ucsd.edu.

Language: Английский

Citations

18
A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank DOI Open Access
Celine A. Manigbas,

Bharati Jadhav,

Paras Garg

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 23, 2024

Abstract Most genetic association studies focus on binary variants. To identify the effects of multi-allelic variation tandem repeats (TRs) human traits, we performed direct TR genotyping and phenome-wide in 168,554 individuals from UK Biobank, identifying 47 TRs showing causal associations with 73 traits. We replicated 23 31 (74%) these All Us cohort. While this set included several known repeat expansion disorders, novel found were attributable to common polymorphic length rather than rare expansions include e.g. a coding polyhistidine motif HRCT1 influencing risk hypertension poly(CGC) 5’UTR GNB2 heart rate. Causal strongly enriched for local gene expression DNA methylation. Our study highlights contribution “missing heritability” genome.

Language: Английский

Citations

6
The emerging role of tandem repeats in complex traits DOI
Michael Lamkin, Melissa Gymrek

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(7), P. 452 - 453

Published: May 7, 2024

Language: Английский

Citations

5
Ribosomal DNA copy number variation associates with hematological profiles and renal function in the UK Biobank DOI Creative Commons
Francisco Rodríguez-Algarra, David M. Evans, Vardhman K. Rakyan

et al.

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(6), P. 100562 - 100562

Published: May 14, 2024

The phenotypic impact of genetic variation repetitive features in the human genome is currently understudied. One such feature multi-copy 47S ribosomal DNA (rDNA) that codes for rRNA components ribosome. Here, we present an analysis rDNA copy number (CN) UK Biobank (UKB). From first release UKB whole-genome sequencing (WGS) data, a discovery White British individuals reveals CN associates with altered counts specific blood cell subtypes, as neutrophils, and estimated glomerular filtration rate, marker kidney function. Similar trends are observed other ancestries. A range analyses argue against reverse causality or common confounder effects, all core results replicate second WGS release. Our work demonstrates influence on trait variance humans.

Language: Английский

Citations

5